A Study to Determine the Efficacy, Safety and Tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) Versus Meropenem (MER) ± Colistin (COL) for the Treatment of Serious Infections Due to Gram Negative Bacteria.

Inclusion Criteria

All subjects:

• Male or female from 18 years of age
• Provision of informed consent
• Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment
• Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met and negative pregnancy test

Additional for cIAI:

• Diagnosis of cIAI, EITHER:

Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry

• Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug

Additional for HAP/VAP:

• Onset symptoms > 48h after admission to or 30
• Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species
• Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure)
• History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the study drugs
• Known Clostridium difficle associated diarrhoea
• Requirement for effective concomitant systemic antibacterials or antifungals
• Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy
• Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure
• Hepatic disease as indicated by AST or ALT >3 × ULN. Patients with AST and/or ALT up to 5 × ULN are eligible if acute and documented by the investigator as being directly related infectious process
• Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease
• ALP >3 × ULN. Patients with values >3 × ULN and <5 x ULN are eligible if acute and directly related to the infectious process being treated
• Absolute neutrophil count <500/mm3
• Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control.
• Any other condition that may confound the results of the study or pose additional risks to the subject
• Unlikely to comply with protocol
• History of epilepsy or seizure disorders excluding febrile seizures of childhood

Additional for cIAI

• Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery < 24 hours of diagnosis primary etiology is not likely to be infectious
• Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess
• Prior liver, pancreas or small-bowel transplant
• Staged abdominal repair (STAR), open abdomen technique or marsupialisation

Additional for HAP/VAP

• APACHE II score < 10
• Known or high likelihood of Gram-positive monomicrobial infection
• Lung abscess, pleural empyema, post-obstructive pneumonia
• Lung or heart transplant
• Myasthenia gravis